Mixed Donor Research Articles

Early Mixed Donor Chimerism is a Strong Negative Prognostic Indicator in Allogeneic Stem Cell Transplant for AML and MDS

Allogeneic bone marrow transplantation remains the most potent curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) due to the graft-versus-tumor effect provided by donor cells. Donor chimerism is utilized early after transplantation to evaluate engraftment and to monitor the persistence of donor hematopoiesis. Literature is conflicting regarding to the prognostic utility of early mixed donor chimerism, chimerism kinetic patterns as well as factors associated with it and we sought to clarify this uncertainty. In this single-centre retrospective analysis, 141 adults aged 18 years of age or older with AML (n = 104) and MDS (n = 37) who received their first transplant from HLA matched related, matched unrelated or mismatched related (haploidentical) donors between 2016 and 2022 and had at least day 30 chimerism measured were included. Approximately 30% received post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis and 67% of subjects received reduced-intensity conditioning. Chimerism was measured using STR-PCR from unfractionated peripheral blood mononuclear cells (whole blood; WB) and CD3+ (T cell; TC) compartment at each time point. Complete donor chimerism was defined as ≥95% whereas <95% defined as mixed. Competing risk analysis was used to estimate cumulative incidence of relapse with kinetic calculations completed using an increment factor. Kaplan-Meier was used for overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to explore prognostic factors for OS and RFS. Both day 30 mixed WB and TC donor chimerism were individually associated with an increased risk of relapse and worse overall and relapse-free survival at days 30, 60 and 90 post-transplant. Day 30 mixed WB was more specific for relapse (86%), while mixed TC was more sensitive (67%). Complete day 30 chimerism had a negative predictive value of 63% and 70% and positive predictive value of 57% and 67% for WB and TC, respectively. Day 30 WB and TC donor chimerism of <88.92% and 89.29% had specificities of 79.17% and 82.19% although sensitivities only approximated 50%. Evaluating the kinetics of chimerism over the first 90 days provided additional information for prognosticating relapse than absolute chimerism values at individual time points in both WB day 30 to 90 [HR, 1.75 (95% CI, 1.04 to 2.94); P < .035] and TC day 60 to 90 [HR, 1.32 (95% CI, 1.03, 1.69); P < .29]. Twice as many patients with complete chimerism developed acute GVHD compared to those with mixed chimerism. Factors that were found to be associated with day 30 mixed TC chimerism were donor source, ATG GVHD prophylaxis, myeloablative conditioning and female sex, while only donor source was associated with mixed WB. Both TC and WB day 30 mixed chimerism were associated with an increased risk of relapse. Early mixed WB and TC chimerism is strongly associated with a worse overall and relapse-free survival. The serial measurement of chimerism early post-transplant for monitoring chimerism kinetics provides additional prognostic information beyond the absolute donor chimerism value at a single time point. Haploidentical stem cell transplants were associated with a lower likelihood of mixed chimerism than other donor sources.

Successful third transplant for recurrent leukemia after TLI-ATG conditioning and despite EBV-associated mixed donor chimerism

Successful third transplant for recurrent leukemia after TLI-ATG conditioning and despite EBV-associated mixed donor chimerism

Enhanced mixed donor chimerism analysis with digital PCR

Enhanced mixed donor chimerism analysis with digital PCR

Achieving High Efficiency and Stability in Organic Photovoltaics with a Nanometer-Scale Twin p-i-n Structured Active Layer.

In pursuing high stability and power conversion efficiency for organic photovoltaics (OPVs), a sequential deposition (SD) approach to fabricate active layers with p-i-n structures (where p, i, and n represent the electron donor, mixed donor:acceptor, and electron acceptor regions, respectively, distinctively different from the bulk heterojunction (BHJ) structure) has emerged. Here, we present a novel approach that by incorporating two polymer donors, PBDBT-DTBT and PTQ-2F, and one small-molecule acceptor, BTP-3-EH-4Cl, into the active layer with sequential deposition, we formed a device with nanometer-scale twin p-i-n structured active layer. The twin p-i-n PBDBT-DTBT:PTQ-2F/BTP-3-EH-4Cl device involved first depositing a PBDBT-DTBT:PTQ-2F blend under layer and then a BTP-3-EH-4Cl top layer and exhibited an improved power conversion efficiency (PCE) value of 18.6%, as compared to the 16.4% for the control BHJ PBDBT-DTBT:PTQ-2F:BTP-3-EH-4Cl device or 16.6% for the single p-i-n PBDBT-DTBT/BTP-3-EH-4Cl device. The PCE enhancement resulted mainly from the twin p-i-n active layer's multiple nanoscale charge carrier pathways that contributed to an improved fill factor and faster photocurrent generation based on transient absorption studies. The PBDBT-DTBT:PTQ-2F/BTP-3-EH-4Cl film possessed a vertical twin p-i-n morphology that was revealed through secondary ion mass spectrometry and synchrotron grazing-incidence small-angle X-ray scattering analyses. The thermal stability (T80) at 85 °C of the twin p-i-n PBDBT-DTBT:PTQ-2F/BTP-3-EH-4Cl device surpassed that of the single p-i-n PBDBT-DTBT/BTP-3-EH-4Cl devices (906 vs 196 h). This approach of providing a twin p-i-n structure in the active layer can lead to substantial enhancements in both the PCE and stability of organic photovoltaics, laying a solid foundation for future commercialization of the organic photovoltaics technology.

Abstract 5334: Humanization of NOG mice and next-generation NOG strains to induce lineage-specific differentiation of immune cells for assessment of novel immune cell therapies, check point inhibitors, and immune cell engagers for translational immuno-oncology research

Abstract Background: The preclinical evaluation of novel immune therapies requires humanized immune system (HIS) mouse models. In previous studies we have demonstrated that either peripheral blood mononuclear cells (PBMC), subsets of PBMCs like T and NK cells or CD34+ hematopoietic stem cells (HSC) can be used to establish a HIS model. With the development of next-generation NOG mice, lineage-specific differentiation of immune cell sub-populations of interest can be supported. Transplantation of cell line-derived (CDX) or patient-derived (PDX) tumor xenografts on HIS mice provides a full model for human tumors for the investigation of checkpoint inhibitors (CPI), as well as novel cell therapies and immune cell engagers. Methods: HSC-humanized mice were generated by i.v. transplantation of CD34+ stem cells to immunodeficient mice. For humanization, NOG mice and next-generation NOG strains were used: NOG, NOG-EXL, hIL-2 NOG, hIL-6 NOG and FcResolv™ NOG mice were compared to each other for lineage-specific differentiation using single donors or a mixed HSC donor pool. Engraftment of immune cells was monitored by FACS analysis of blood every four weeks. In humanized NOG mice, CDX and PDX from different entities were s.c. transplanted and used to evaluate CPI. Results: Humanized hIL-2 NOG mice showed significantly decreased survival after HSC transplantation in comparison to the other mouse strains and had to be sacrificed within the first 6-8 weeks after HSC transplantation. In the other mouse strains, transplanted HSCs engrafted and differentiated mainly into B and T cells. NOG-EXL mice displayed the highest engraftment, with up to 80% of human cells in the blood, including a higher portion of myeloid cells. In humanized hIL-6 NOG mice a higher portion of monocytes could be determined. FcResolv™ NOG mice lack murine Fc gamma receptors in order to reduce confounding interactions between residual murine immune cells and antibody-based therapies, and they engraft and differentiate human HSCs similarly to the parent NOG strain. In humanized NOG mice, selected CDX and PDX tumors successfully engrafted without significant differences in tumor growth compared to non-humanized mice. CPI treatments induced tumor growth delay in selected models. Conclusions: Next-generation NOG mouse strains are characterized by a lineage-specific differentiation of immune cells depending on integrated human cytokines. Furthermore, we established a human tumor-immune-cell model for NOG mice using different entities of CDX or PDX in combination with CPI. Our human tumor-immune cell models allow preclinical translational studies on tumor immune biology as well as evaluation of new therapies, drug combinations and biomarker identification and validation. Citation Format: Maria Stecklum, Louise Baskin, Jens Hoffmann. Humanization of NOG mice and next-generation NOG strains to induce lineage-specific differentiation of immune cells for assessment of novel immune cell therapies, check point inhibitors, and immune cell engagers for translational immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5334.

π-π Stacking Modulation via Polymer Adsorption for Elongated Exciton Diffusion in High-Efficiency Thick-Film Organic Solar Cells.

Developing efficient organic solar cells (OSCs) with thick active layers is crucial for roll-to-roll printing. However, thicker layers often result in lower efficiency. This study tackles this challenge using a polymer adsorption strategy combined with a layer-by-layer approach. Incorporating insulator polystyrene (PS) into the PM6:L8-BO system creates PM6+PS:L8-BO blends, effectively suppressing trap states and extending exciton diffusion length in the mixed donor domain. Adding insulating polymers with benzene rings to the donor enhances π-π stacking of donors, boosting intermolecular interactions and electron wave function overlap. This results in more orderly molecular stacking, longer exciton lifetimes, and higher diffusion lengths. The promoted long-range exciton diffusion leads to high power conversion efficiencies of 19.05% and 18.15% for PM6+PS:L8-BO blend films with 100 and 300nm thickness, respectively, as well as a respectable 16.00% for 500nm. These insights guide material selection for better exciton diffusion, and offer a method for thick-film OSC fabrication, promoting a prosperous future for practical OSC mass production.

In vivo measurement of RBC survival in patients with sickle cell disease before or after hematopoietic stem cell transplantation

AbstractStable, mixed-donor–recipient chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD) is sufficient for phenotypic disease reversal, and results from differences in donor/recipient–red blood cell (RBC) survival. Understanding variability and predictors of RBC survival among patients with SCD before and after HSCT is critical for gene therapy research which seeks to generate sufficient corrected hemoglobin to reduce polymerization thereby overcoming the red cell pathology of SCD. This study used biotin labeling of RBCs to determine the lifespan of RBCs in patients with SCD compared with patients who have successfully undergone curative HSCT, participants with sickle cell trait (HbAS), and healthy (HbAA) donors. Twenty participants were included in the analysis (SCD pre-HSCT: N = 6, SCD post-HSCT: N = 5, HbAS: N = 6, and HbAA: N = 3). The average RBC lifespan was significantly shorter for participants with SCD pre-HSCT (64.1 days; range, 35-91) compared with those with SCD post-HSCT (113.4 days; range, 105-119), HbAS (126.0 days; range, 119-147), and HbAA (123.7 days; range, 91-147) (P<.001). RBC lifespan correlated with various hematologic parameters and strongly correlated with the average final fraction of sickled RBCs after deoxygenation (P<.001). No adverse events were attributable to the use of biotin and related procedures. Biotin labeling of RBCs is a safe and feasible methodology to evaluate RBC survival in patients with SCD before and after HSCT. Understanding differences in RBC survival may ultimately guide gene therapy protocols to determine hemoglobin composition required to reverse the SCD phenotype as it relates directly to RBC survival. This trial was registered at www.clinicaltrials.gov as #NCT04476277.

Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation. Surprisingly, this treatment had a positive impact on mixed chimerism with an increase of donor-cell proportions from 40% for neutrophils and 75% for non-T-mononuclear cells (MNCs) to >90% for both. T-cell counts remained stable with 100% of donor origin. This is -to our knowledge- the first report on the impact of cytoreductive chemotherapy on post-HSCT mixed chimerism and provides an important first impression for future patients.

Macrocyclic complexes of Fe(III) with mixed hydroxypropyl and phenolate or amide pendants as T1 MRI probes.

High-spin Fe(III) complexes of 1,4,7-triazacyclononane (TACN) with mixed oxygen donor pendants including hydroxypropyl, phenolate or amide groups are prepared for study as T1 MRI probes. Complexes with two hydroxypropyl pendants and either amide (Fe(TOAB)) or phenolate (Fe(PTOB)) groups are compared to an analog with three hydroxypropyl groups (Fe(NOHP)), in order to study the effect of the third pendant on the coordination sphere as probed by solution chemistry, relaxivity and structural studies. Solution studies show that Fe(PTOB) has two ionizations with the phenol pendant deprotonating with a pKa of 1.7 and a hydroxypropyl pendent with pKa of 6.3. The X-ray crystal structure of [Fe(PTOB)]Br2 features a six-coordinate complex with two bound hydroxypropyl groups, and a phenolate in a distorted octahedral geometry. The Fe(TOAB) complex has a single deprotonation, assigned to a hydroxypropyl group with a pKa value of 7.0. Both complexes are stabilized as high-spin Fe(III) in solution as shown by their effective magnetic moments and Fe(III)/Fe(II) redox potentials of -390 mV and -780 mV versus NHE at pH 7 and 25 °C for Fe(TOAB) and Fe(PTOB) respectively. Both Fe(PTOB) and Fe(TOAB) are kinetically inert to dissociation under a variety of challenges including phosphate/carbonate buffer, one equivalent of ZnCl2, two equivalents of transferrin or 100 mM HCl, or at basic pH values over 24 h at 37 °C. The r1 relaxivity of Fe(TOAB) at 1.4 T, pH 7.4 and 33 °C is relatively low at 0.6 mM-1 s-1 whereas the r1 relaxivity of Fe(PTOB) is more substantial and shows an increase of 2.5 fold to 2.5 mM-1 s-1 at acidic pH. The increase in relaxivity at acidic pH is attributed to protonation of the phenolate group to provide an additional pathway for proton relaxation.

PdII Triazolylidene Complexes: Ancillary Ligand Dependent Catalytic Applications in Sonogashira Coupling and α‐Arylation Reactions under Copper‐Free Conditions

AbstractComplexes ofN‐heterocyclic carbenes have become an irrefutable class of molecules for the researchers in the field of organocatalysis. They rank as one of the potent tools in organic chemistry, which have a wide range of uses in various commercially important processes. Palladium(II) mesoionic carbene (MIC) complexes embedded with PPh3 as an ancillary ligand appeared to be efficient catalysts for the aforementioned purpose. Two new triazolylidene‐based palladium(II) complexes bearing either Py or PPh3 as an ancillary ligand were synthesized, with chirality present at one of the nitrogen atoms of the triazolylidene moiety. The MIC unit in these complexes possesses a mesityl group at the C‐wingtip and 1‐(1‐naphthyl)ethyl substitution at the N‐wingtip. NMR spectroscopy and ESI mass spectrometry were utilized to analyze these complexes. For the determination of the structure of the palladium(II) complex possessing mixed MIC and PPh3 donor ligands, single crystal X‐ray diffraction was utilized. The new complexes were employed in α‐arylation reaction and Sonogashira coupling reactions under copper‐free conditions. While studying their catalytic activity, it was brought to the conclusion that the PdII MIC complex having PPh3 as an ancillary ligand surpassed the complex with Py as an ancillary ligand.The catalytic results of these complexes are also correlated with cyclic voltammetric (CV) data.

VLA-4 Agonist Enhances the Capacity of HSC Engraftment and Immune Reconstitution

Poor donor cell implantation and delayed hematopoietic reconstitution are important factors affecting the prognosis of patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, our understanding of the critical endogenous signals that reconstitute hematopoiesis in transplant patients remains limited，which is essential for achieving targeted interventions and preventing donor-recipient chimeric states after transplantation. Here, we revealed the reconstitution dynamics of human allogeneic hematopoietic stem and progenitor cells (HSPCs) and immune cell subpopulations in the post-transplantation mixed donor chimerism (MDC) to fully donor chimerism (FDC) state at single-cell resolution. The hematopoietic stem cell (HSC) implantation process involves extensive interactions with immune cells mainly through surface Kcnq5, Itga4 (encoding a subunit of VLA-4), Tfrc, CD44 receptor, and ligands for Rps19, B2m, etc. Further identification of VLA-4(integrin α4β1) as a potential regulatory target for HSC implantation by single-cell sequencing of a stable allogeneic bone marrow transplantation (Allo-BMT) MDC-FDC mouse model. Grafts Itgα4 and Itgβ1 deletion impair donor implantation and further diminish the efficacy of donor lymphocyte infusion (DLI) following Allo-BMT, rather than directly affecting DLI. Critically, we identified a VLA-4 agonist that promotes donor implantation in the mixed chimeric mouse model of Allo-BMT in a time-dependent manner, with the most pronounced promotion of early T cell implantation in particular. Moreover, it was found to enhance the self-renewal capacity of HSC and lymphoid reconstitution in competitive transplantation and human umbilical cord blood transplantation xenograft experiments. Fortunately, VLA-4 agonist does not exacerbate the acute graft-versus-host disease(aGVHD) process while maintaining the graft-versus-leukemia (GVL) effect. VLA-4 agonist not only upregulates of both Itgα4 and Itgβ1 expression, but also promotes the ERK/2 phosphorylation pathway, which affects HSC biological functions, and this process can be inhibited by ERK kinase inhibitors. These results provide insights into the regenerative process of transplanted HSPCs in human patients，and demonstrate a previously unknown positive regulation of HSC engraftment and immune reconstitution by VLA-4, and allow for a new and simple translational strategy to enhance HSC transplantation.

Analysis of the Impact of Whole Blood and T-Cell Donor Chimerism after Allogeneic Stem Cell Transplant

Background: Allogeneic stem cell transplant (alloSCT) is one of the few currently available therapies to cure acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Positive outcomes are dependent on engraftment of donor cells to provide hematopoiesis as well as a graft-versus-tumor effect. Measurement of whole blood (WB) and T-cell (TC) chimerism at routine intervals post alloSCT allows for monitoring of engraftment. Development of mixed donor chimerism (MC) may indicate impending graft failure or disease relapse. The ideal frequency for chimerism measurements as well as the role of WB versus TC chimerism remains unclear. In this study, we analyzed the impact of WB versus TC mixed chimerism on survival outcomes in patients with AML and MDS. Furthermore, we studied baseline factors associated with the development of MC. Methods: In this retrospective analysis, adults with AML or MDS who received an alloSCT between January 1, 2016 and February 1, 2022 that had at least 1 donor chimerism measured on Day 30 (D30), Day 60 (D60), Day 90 (D90) at Juravinski Hospital and Cancer Centre (Hamilton, ON, Canada). Baseline demographic and transplant-related characteristics were collected. AML and MDS diagnoses were based on WHO 2016 classification of myeloid neoplasm and acute leukemia. Conditioning intensities were classified according to CIBMTR definitions. A total of 271 transplants were completed during the study period for AML or MDS. 128 were excluded from the analysis (chimerism testing not performed (n=121), second transplants (n=7)). We analyzed a total of 143 patients with median age of 63 years (19 - 76) who were transplanted for AML (n=105) and MDS (n=38). Donors were HLA-matched siblings (MRD, n=26), unrelated donors (MUD (8/8 or 7/8), n=85) or haploidentical related donor (MMRD, n=32). All patients except one received peripheral blood stem cell grafts. For alloSCT, 20 % of patients received myeloablative conditioning (MAC) and 80% received reduced-intensity conditioning (RIC). Complete chimerism (CC) was defined as ≥95%, whereas MC was defined as ≤95%. All chimerism measurements were measured using a PowerPlex® 16 System (Promega) (Hamilton Regional Laboratory Medicine Program, Hamilton, ON). Results: In our cohort, OS at 2 years was 57% and RFS 49%. Of the baseline factors, only disease-risk based on ELN 2022 for RFS with a hazard ratio (HR) of 1.43, 95% CI [0.83, 2.49] for adverse risk and HR 0.53 95% CI [0.23, 1.03] (p=0.03) for favourable risk. WB MC was detected in 22%, 22%, 23% of patients on D30, D60, and D90, respectively. TC MC was detected in 48%, 46%, and 43% of patients on D30, D60, and D90, respectively. WB MC had a strong negative impact on RFS, with a HR of 2.81, 95% CI [1.69, 4.66; p&amp;lt;0.001] on D30, 3.07, 95% CI [1.67, 5.66; p&amp;lt;0.001] on D60 and 4.77, 95% CI [2.47, 9.22; p&amp;lt;0.001] on D90. The influence of TC MC on RFS was also significant at all time points. Of 101 patients who were alive and did not have a relapse prior to D90 and had D30 chimerism and D90 chimerism evaluated, the patients who had a mixed WB and TC chimerism on D90 had a HR of 6.13, 95% CI [2.23, 16.85] and HR 2.73, 95% CI [1.24, 5.98] for RFS, which was statistically significant even after adjusting for known information of D30 WB/TC chimerism status (Table 1). WB MC had a strong negative impact on OS with a HR of 2.67, 95% CI (1.54, 4.64; p=0.001) on D30, 2.81, 95% CI (1.47, 5.38; p=0.002) on D60 and 4.78, 95% CI (2.47, 9.24; p&amp;lt;0.001) on D90. Again, the later time points remained statistically significant, when adjusting for known D30 chimerism status. The influence of TC MC on OS was also significant at all time points, however only a non-significant trend remained at later time points when adjusting for D30 TC chimerism (Table 2). We analyzed baseline factors predictive for D30 chimerism. For WB chimerism, only donor source remained statistically significant (p=0.038) with MMRD having a lower HR for MC 0.39, 95% CI [0.11, 1.41] and MRD having a higher HR for MC 2.33, 95% CI [0.9 - 5.99]. Conclusions: Our data confirm that a mixed chimerism as early as D30 post-alloSCT can have a detrimental impact on outcomes (RFS and OS) in alloSCT. Patients receiving haploidentical alloSCT had a lower risk to develop mixed chimerism in our cohort. These dismal outcomes of patients with mixed chimerism in our cohort provides a strong rationale to study interventions such as novel maintenance strategies or donor-lymphocyte infusions in this patient group.

Roles of Blend Morphology and Energy Level Alignment in Determining Open‐Circuit Voltage and Fill Factor of Ternary All‐Polymer Solar Cells

AbstractTuning the open‐circuit voltage (VOC) and fill factor (FF) without sacrificing the short‐circuit current density is crucial for achieving performance advantages in ternary blend organic solar cells as an alternative to the binary ones. This study investigates ternary all‐polymer solar cells comprised of two polymer donors (D1 and D2) and one polymer acceptor (A), using two types of D2 polymers with different compatibilities with D1. As demonstrated by photoelectron yield spectroscopy, the ionization energy (IE) of the ternary blends continuously shifts between the IEs of D1:A and D2:A binary blends when D2 forms a single indistinguishable domain with D1. In contrast, the IE of the blends does not exhibit any noticeable change when D2 induces distinct phase separation with D1. Models describing the blend composition dependence of the VOC and FF are constructed by correlating the effects of the blend morphology and the shift in the energy level of the hole‐transporting state in the ternary blends. This study demonstrates that a pseudo‐binary blend morphology with a mixed D1 and D2 donor domain and an A acceptor domain is necessary to obtain a broad tunability of VOC and tolerance of FF to the blend composition in ternary all‐polymer solar cells.

Osteoarthritis Disease Severity in the Temporomandibular Joint and the Knee Joint: A Comparative Cadaveric Study.

The objective of this study was to determine the level of disease severity in a pilot cohort of temporomandibular joints (TMJs) and compare them to the pathology findings previously characterized in cadaveric knee joints. Thirty-one intact TMJs from 17 cadaveric donors were harvested and arthritic lesioning seen in the knee joint was investigated on the condyle and the fossa of the TMJ. Prevalence of gross alterations was equated and disease severity was determined for sex- and age-based donor pools using a validated, osteoarthritis (OA) disease severity scale (DSS). Knee joint DSS scores were also compared to the TMJ condyle and fossa DSS scores and a case study was carried out on a male donor that demonstrated severe OA in the both joints. The mandibular fossa demonstrated an increase in disease severity compared to the mandibular condyle in a mixed sex donor pool (P = 0.035). It was discovered that the younger females demonstrated statistically more pathological condyles compared to the older half of the female subgroup (P = 0.02). TMJ fossa and knee joints demonstrated comparable OA severity and similar signs of cartilage disease in a single donor highlighting the systemic nature of OA. This study demonstrates that gross signs of OA in the TMJs of cadavers are comparable to pathology found in the knee. The mandibular fossa appears to be the site of more profound disease, implying translational movements may be more likely to induce biomechanically abnormal movement, loading, and OA.

Chemobiocatalytic transfromation of biomass into furfurylamine with mixed amine donor in an eco-friendly medium

Biobased furfurylamine (FAM) is a versatile platform molecule for producing additives, pharmaceuticals, and pesticides. Recombinant E. coli HNND-AlaDH was created by co-expressing L-alanine dehydrogenase (AlaDH) and mutated Aspergillus terreus ω-transaminase (HNND), aiming to convert furfural (FUR) into FAM using inexpensive L-alanine and isopropylamine as mixed amine donors. In ChCl:FA:OA (10 wt%), pineapple peel, bagasse, barley shell, peanut shell, and corn stalk could be efficiently transformed into FUR under 170 °C for 10 min. Pineapple peel produced a high titer of FUR (183.3 mM). Additionally, the viscosity, surface tension and polarity of ChCl:FA:OA were explored. The biomass-derived FUR was fully transformed to FAM by HNND-AlaDH with amine donor (1:1:1 of L-Ala/isopropylamine/FUR mol/mol/mol) within 300 min. Accordingly, the FAM productivity was 0.58 g/(g xylan in pineapple peel). This chemobiocatalytic strategy established through the combination of chemocatalysis and biocatalysis could be applied to convert renewable biomass into valuable organic amines.

Posttransplant MRD and T-cell chimerism status predict outcomes in patients who received allografts for AML/MDS.

Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P= .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P< .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P=.0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P= .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.

Triplet-Encoded Prebiotic RNA Aminoacylation.

The encoding step of translation involves attachment of amino acids to cognate tRNAs by aminoacyl-tRNA synthetases, themselves the product of coded peptide synthesis. So, the question arises─before these enzymes evolved, how were primordial tRNAs selectively aminoacylated? Here, we demonstrate enzyme-free, sequence-dependent, chemoselective aminoacylation of RNA. We investigated two potentially prebiotic routes to aminoacyl-tRNA acceptor stem-overhang mimics and analyzed those oligonucleotides undergoing the most efficient aminoacylation. Overhang sequences do not significantly influence the chemoselectivity of aminoacylation by either route. For aminoacyl-transfer from a mixed anhydride donor strand, the chemoselectivity and stereoselectivity of aminoacylation depend on the terminal three base pairs of the stem. The results support early suggestions of a second genetic code in the acceptor stem.

Tuning the Alkyl Chain of Nitrilotriacetamide for Selectively Extracting Trivalent Am over Eu Ions.

The successful management and safe disposal of high-level nuclear waste necessitate the efficient separation of actinides (An) from lanthanides (Ln), which has emerged as a crucial prerequisite. Mixed donor ligands incorporating both soft and hard donor atoms have garnered interest in the field of An/Ln separation and purification. One such example is nitrilotriacetamide (NTAamide) derivatives, which have demonstrated selectivity in extracting minor actinide Am(III) ions over Eu(III) ions. Nevertheless, the Am/Eu complexation behavior and selectivity remain underexplored. In the work, a comprehensive and systematic investigation has been conducted for [M(RL)(NO3)3] complexes (M = Am and Eu) utilizing relativistic density functional theory. The NTAamide ligand (RL) is substituted with various alkyl groups, namely, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Thermodynamic calculations show that the alkyl chain length in NTAamide is capable of tuning the separation selectivity of Am and Eu. Moreover, the differences in calculated free energies between Am and Eu complexes are more negative for R = Bu-Oct than Me-Pr. This indicates that elongation of the alkyl chain can increase the efficiency of selective separation of Am(III) from Eu(III). Based on the quantum theory of atoms in molecules and charge decomposition analyses, it has been observed that the strength of Am-RL bonds is higher than that of Eu-RL bonds. This disparity is attributed to a greater degree of covalency in Am-RL bonds and a higher level of charge transfer from ligands to Am within complexes containing these bonds. Energies of occupied orbitals with the central N character are recognized overall lower for [Am(OctL)(NO3)3] than for [Eu(OctL)(NO3)3], indicative of stronger complexation stability of the former. These results offer valuable insights into the separation mechanism of NTAamide ligands, which can help guide the development of more powerful agents for An/Ln separation in future applications.

Silver(I) coordination polymers based on nitrile-functionalized mixed-donor ligands of different flexibility

The nitrile-functionalized derivatives of 2,8-dithia-5-aza-2,6-pyridinophane ([12]anePyNS2)(Py = Pyridine), 1-aza-4,7,10-trithiacyclododecane ([12]aneNS3), and N,N’-bis(2-pyridylmethyl)-propylenediamine (Pypn), referred to as L10, L11 and L12, respectively, have been prepared. Following the reaction of these ligands with silver(I) salts, the three coordination polymers (CPs) {[Ag(L10)](BF4)}∞, {[Ag(L11)](BF4)∙½MeCN}∞, and {[Ag(L12)](NO3)}∞, have been isolated and structurally characterized. The structural features of the three CPs depends more on the nature of the un-functionalized ligands rather than on the presence of the nitrile groups. A comparative analysis of the structures of the three CPs is performed in relation to the structures of polymeric silver(I) compounds obtained with nitrile-functionalized pendant arms of related aza- and mixed donor macrocyclic ligands (L1–L9) reported in the literature.

Two Electron Multicenter Bonding (Pancake Bonding) between Electron Donors and Acceptors in Charge-Transfer Compounds ofN,N,N′,N′-Tetramethyl-p-phenylenediamine and (Semi)quinoid Electron Acceptors

Five charge transfer complexes of electron donor N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD or Wurster’s blue) with quinoid electron acceptors tetrafluoro- (F4Q), tetrachloro- (Cl4Q), tetrabromoquinone (Br4Q), 7,7,8,8-tetracyanoquinodimethane (TCNQ), and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) were prepared and studied by X-ray crystallography, impedance spectroscopy, and DFT computations. Mixed donor–acceptor π-stacks were observed in all compounds; in TMPD·F4TCNQ, the moieties formed 2D stacked arrays. All moieties had a partial radical character due to charge transfer. The presence of two-electron multicenter bonding (pancake bonding) was confirmed by quantum chemical computation. In TMPD·F4Q, alternating longer and shorter interplanar distances were consistent with formation of pancake-bonded dimers; in complexes of TMPD with Cl4Q, Br4Q, and TCNQ, the stacks were equidistant implying existence of pancake-bonded polymers.